Metformin in Intrahepatic Cholestasis of Pregnancy (METRIC)

METformin in Intrahepatic Cholestasis of Pregnancy (METRIC) Study

This is a pilot study aimed at comparing the effect of metformin versus ursodeoxycholic acid in women with intrahepatic cholestasis in pregnancy. The study will be conducted in three NHS hospital sites, over an 18 month period.

Study Overview

• Status: Unknown
• Conditions: Pregnancy Complications; Intrahepatic Cholestases
• Intervention / Treatment: Drug: Ursodeoxycholic Acid; Drug: Metformin

Detailed Description

Intrahepatic cholestasis is a condition that affects pregnant women. It is characterised by itching, usually in the third trimester of pregnancy and is associated with an increase in the liver enzymes and bile salts. This can be associated with maternal and neonatal morbidity, and rarely perinatal mortality.

The investigators propose to assess and compare the effect of Metformin versus Ursodeoxycholic acid on lowering liver enzymes and bile salts, improving maternal morbidity and improving neonatal outcomes.

This study is a pilot study that will be conducted at 3 NHS hospital sites where patients will randomly assigned to receive either Metformin or Ursodeoxycholic acid. There will be 20 patient in each arm. Recruitment will commence in February 2017 and will run for an 18 month period.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Hassan Shehata, FRCPI, FRCOG; Phone Number: 6887 01372 735735; Email: hassan.shehata@esth.nhs.uk
• Study Contact Backup: Name: Amanda Ali, MRCPI, MRCOG; Email: amandaha.ali@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. 20+0 to 40 weeks' gestation on day of randomisation
2. Itching with a raised serum bile acid above the upper limit of normal
3. Normal anomaly scan at 20 weeks
4. Aged 18 years or over
5. Able to give written informed consent
6. No known pre-existing liver disease

Exclusion Criteria:

1. Decision already made for delivery within the next 48 hours
2. Known allergy to any component of the ursodeoxycholic acid or metformin tablets
3. Patients already on metformin for other conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin arm; Metformin	Drug: Ursodeoxycholic Acid; Ursodeoxycholic acid (UDCA) is used to treat gallstones and primary biliary cirrhosis. UDCA is also used to treat obstetric cholestasis (OC), a liver condition that occurs specifically in pregnancy.; Other Names: Destolit®, Urdox®, Ursofalk®, Ursogal®
Active Comparator: Ursodeoxycholic acid	Drug: Metformin; Metformin Hydrochloride (HCl) Tablets, is an oral antihyperglycemic drug used in the management of type 2 diabetes; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normalisation of maternal serum concentration of bile salts and liver enzymes	Normalisation of Bile acids and liver enzymes - both parameters are the cornerstone for a diagnosis of intrahepatic cholestasis. They have been separated into two outcomes due to to the different laboratory indices of measurement. Results will be aggregated together to report number of patients with abnormal results	From date of randomisation to date of delivery assessed up to 26 weeks
Normalisation of maternal serum concentration of liver enzymes	Normalisation of liver enzymes Alanine transaminase Aspartate transaminase Bilirubin (total) Gamma glutamyl transferase Results will be aggregated together to report the number of patients with abnormal liver enzymes	From date of randomisation to date of delivery assessed up to 26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fetal outcomes	Perinatal death	From date of randomisation to date of delivery assessed up to 26 weeks
Fetal outcomes	Preterm delivery	From date of randomisation to date of delivery assessed up to 26 weeks
Fetal outcomes	Respiratory distress syndrome	Immediately upon delivery date
Fetal outcomes	Birth weight (g)	Immediately upon delivery date
Fetal outcomes	Birth weight percentile	Immediately upon delivery date
Fetal outcomes	Gestational age at delivery	Immediately upon delivery date

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fetal outcomes	Presence of meconium	Immediately upon delivery date
Fetal outcomes	APGAR score at 5 minutes	Immediately upon delivery date
Fetal outcomes	Umbilical arterial pH at birth	Immediately upon delivery date
Maternal outcomes	Symptoms (itch) - assessed by questionnaire at clinic visits	From date of randomisation to date of delivery assessed up to 26 weeks
Maternal outcomes	Maximum dose of medication required	From date of randomisation to date of delivery assessed up to 20 weeks
Maternal outcomes	Gestational diabetes	From date of randomisation to date of delivery assessed up to 20 weeks
Maternal outcomes	Postpartum haemorrhage	From date of randomisation to date of delivery assessed up to 26 weeks
Maternal outcomes	Mode of delivery	From date of randomisation to date of delivery assessed up to 20 weeks
Maternal outcomes	Liver failure	From date of randomisation to date of delivery assessed up to 26 weeks

Collaborators and Investigators

• Sponsor: Epsom and St Helier University Hospitals NHS Trust
• Collaborators: King's College Hospital NHS Trust; Medway NHS Foundation Trust
• Investigators: Principal Investigator: Hassan Shehata, FRCPI, FRCOG, Epsom & St Helier University Trust

Publications and helpful links

General Publications

• Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493. doi: 10.1002/14651858.CD000493.pub3.
• Elfituri A, Ali A, Shehata H. Managing Recurring Obstetric Cholestasis With Metformin. Obstet Gynecol. 2016 Dec;128(6):1320-1323. doi: 10.1097/AOG.0000000000001748.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2019
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): September 1, 2019

Study Registration Dates

• First Submitted: December 22, 2016
• First Submitted That Met QC Criteria: February 14, 2017
• First Posted (Actual): February 17, 2017

Study Record Updates

• Last Update Posted (Actual): July 26, 2018
• Last Update Submitted That Met QC Criteria: July 24, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Metformin; Outcomes; Ursodeoxycholic acid
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Pregnancy Complications; Cholestasis; Cholestasis, Intrahepatic; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Cholagogues and Choleretics; Metformin; Ursodeoxycholic Acid
• Other Study ID Numbers: RVR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No